There are very limited pharmacotherapy options for treatment of alcohol use disorders, with only three drugs currently approved for use. Further, these are only modestly effective and not widely prescribed, possibly due to their lack of efficacy. An Important facet of alcohol addiction that is often under-treated is the possibility of relapse. Effective treatment of alcohol addiction and relapse therefore, requires new, broader pharmacological approaches. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide agonist of the opioid receptor-like (ORL 1) receptor (also known as NOP) reduces the rewarding actions of ethanol and prevents reinstatement of ethanol seeking in laboratory animals. Importantly, however, N/OFQ is shown to have anti-anxiety-like and anti-stress-like activity, and functions as a CRF antagonist, to reverse behavioral effects of stress in animal models of alcohol addiction. Therefore, NOP receptor agonism appears to be a broad, promising strategy that may be particularly suitable for treating the various aspects of alcohol addiction. The goal of this contract Is to develop potent and selective NOP agonists, specifically optimized for their drug-like suitability, and to assess the effect of a selected optimized NOP agonist on ethanol-induced conditioned place preference. The outcome of this project will be the identification of efficacious NOP agonist drug candidates, suitable for further development as potential pharmacotherapy for alcohol addiction and relapse prevention.